Within this application several publications are references by arabic numerals within parentheses. Full citations for these and other references may be found at the end of the specification immediately preceding the claims. The disclosures of all of these publication in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Arrhythmias of the heart, such as fibrillation, are well known to those familiar with the heart. Localized or diffuse lesions of the myocardium, which may result from any one of various reasons, often lead to a pronounced dispersion of repolarization and refractoriness. As a result, under certain circumstances the heart does not experience a normal sequential depolarization but, rather, there results an abnormal activation pattern and/or dispersion of repolarization. An abnormal impulse occurring during this period can lead to electrical fragmentation, and consequent initiation of ventricular fibrillation.
It is known that the proper application of an electrical shock to the heart can change a fibrillating heart back to synchronous action of all myocardial fibers; that is, the heart can be defibrillated. Defibrillation induced by electrical shock of the heart results in a regular development of propagation of electrical excitation by means of simultaneous depolarization of all myocardial fibers that have gone out of step to cause the arrhythmia. Many defibrillation devices are known in the prior art for providing a defibrillation pulse after the arrhythmia has commenced.
However, it has become apparent that electrical defibrillation is not an ideal means of therapy for arrhythmia problems. First of all, it is not immediately available in most cases, and even where implantable defibrillation devices are used, they provide stimulation signals only after the dangerous condition of arrhythmia already exists. Further, though implantable defibrillators were developed to eliminate existing ventricular fibrillation as rapidly as possible, they can do so only after detection of the actual state of fibrillation; and because of the high power requirements of the electrical shocks required to defibrillate, the operating time of such implantable defibrillators is highly limited. Further, even after detecting the advent of fibrillation, such prior art defibrillators require a discreet period of charge time before providing a defibrillation shock.
The determinants of myocardial conduction and repolarization include the dimensions and packing geometry of the myocytes, and the properties of the gap junction which are the membrane specializations that form the low resistance pathways for the flow of intercellular current. (1, 2) Changes in quantity and distribution of gap junctions and their constituent proteins, connexins, have been demonstrated in various disease states (3-7) and experimental data indicate that such changes may cause heterogeneous slowing of conduction (8, 9) and are strongly implicated in reentry (10). There is also increasing evidence for the general concept of tachyarrhythmia-induced, and of pacing-induced, electrophysiological remodeling of myocardium. (11, 12) Pacing-induced alterations in activation pathways cause changes in the T wave that long outlast the return to sinus rhythm (13-16), and are generally referred to as “cardiac memory” (13, 17). Given that low resistance connections between cells are the basis for electrotonus, and that electronic current flow modulates the voltage-time course of repolarization of nearby myocytes (18), remodeling of gap-junctional coupling may be implicated in the mechanism of cardiac memory. Changes in conduction and repolarization that occur in circumstances of altered activation may be critical to the pathophysiology of arrhythmias, and both would be facilitated by altered electrotonus that might accompany gap junctional remodeling.